{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T13:04:52Z","timestamp":1772283892262,"version":"3.50.1"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T00:00:00Z","timestamp":1621814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Pediatr Res"],"published-print":{"date-parts":[[2021,10]]},"DOI":"10.1038\/s41390-021-01588-2","type":"journal-article","created":{"date-parts":[[2021,5,24]],"date-time":"2021-05-24T08:03:01Z","timestamp":1621843381000},"page":"744-751","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Juvenile idiopathic arthritis: lymphocyte activation gene-3 is a central immune receptor in children with oligoarticular subtypes"],"prefix":"10.1038","volume":"90","author":[{"given":"Erdal","family":"Sag","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Selcan","family":"Demir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maithri","family":"Aspari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morten Aagaard","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e6cilie","family":"Skej\u00f8","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malene","family":"Hvid","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egemen","family":"Turhan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yelda","family":"Bilginer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stinne","family":"Greisen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seza","family":"Ozen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bent","family":"Deleuran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,5,24]]},"reference":[{"key":"1588_CR1","doi-asserted-by":"publisher","first-page":"2138","DOI":"10.1016\/S0140-6736(11)60244-4","volume":"377","author":"B Prakken","year":"2011","unstructured":"Prakken, B., Albani, S. & Martini, A. Juvenile idiopathic arthritis. Lancet 377, 2138\u20132149 (2011).","journal-title":"Lancet"},{"key":"1588_CR2","first-page":"390","volume":"31","author":"RE Petty","year":"2004","unstructured":"Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J. Rheumatol. 31, 390\u2013392 (2004).","journal-title":"J. Rheumatol."},{"key":"1588_CR3","first-page":"2445","volume":"25","author":"S Ozen","year":"1998","unstructured":"Ozen, S. et al. Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. J. Rheumatol. 25, 2445\u20132449 (1998).","journal-title":"J. Rheumatol."},{"key":"1588_CR4","doi-asserted-by":"publisher","first-page":"1008","DOI":"10.1016\/j.autrev.2017.07.014","volume":"16","author":"R Cimaz","year":"2017","unstructured":"Cimaz, R., Marino, A. & Martini, A. How I treat juvenile idiopathic arthritis: a state of the art review. Autoimmun. Rev. 16, 1008\u20131015 (2017).","journal-title":"Autoimmun. Rev."},{"key":"1588_CR5","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1136\/annrheumdis-2016-210025","volume":"76","author":"A Hinks","year":"2017","unstructured":"Hinks, A. et al. Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann. Rheum. Dis. 76, 765\u2013772 (2017).","journal-title":"Ann. Rheum. Dis."},{"key":"1588_CR6","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1002\/art.40216","volume":"69","author":"LA McIntosh","year":"2017","unstructured":"McIntosh, L. A. et al. Genome-wide association meta-analysis reveals novel juvenile idiopathic arthritis susceptibility loci. Arthritis Rheumatol. 69, 2222\u20132232 (2017).","journal-title":"Arthritis Rheumatol."},{"key":"1588_CR7","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1038\/ng.2614","volume":"45","author":"A Hinks","year":"2013","unstructured":"Hinks, A. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat. Genet. 45, 664\u2013669 (2013).","journal-title":"Nat. Genet."},{"key":"1588_CR8","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1007\/s10875-011-9580-0","volume":"31","author":"N Amariglio","year":"2011","unstructured":"Amariglio, N. et al. T-cell compartment in synovial fluid of pediatric patients with JIA correlates with disease phenotype. J. Clin. Immunol. 31, 1021\u20131028 (2011).","journal-title":"J. Clin. Immunol."},{"key":"1588_CR9","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1093\/intimm\/13.12.1541","volume":"13","author":"LR Wedderburn","year":"2001","unstructured":"Wedderburn, L. R., Patel, A., Varsani, H. & Woo, P. Divergence in the degree of clonal expansions in inflammatory T cell subpopulations mirrors HLA-associated risk alleles in genetically and clinically distinct subtypes of childhood arthritis. Int. Immunol. 13, 1541\u20131550 (2001).","journal-title":"Int. Immunol."},{"key":"1588_CR10","doi-asserted-by":"publisher","first-page":"589641","DOI":"10.3389\/fimmu.2020.589641","volume":"11","author":"S Nussing","year":"2020","unstructured":"Nussing, S., Trapani, J. A. & Parish, I. A. Revisiting T cell tolerance as a checkpoint target for cancer immunotherapy. Front. Immunol. 11, 589641 (2020).","journal-title":"Front. Immunol."},{"key":"1588_CR11","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1016\/j.immuni.2016.04.017","volume":"44","author":"Q Zhang","year":"2016","unstructured":"Zhang, Q. & Vignali, D. A. Co-stimulatory and co-inhibitory pathways in autoimmunity. Immunity 44, 1034\u20131051 (2016).","journal-title":"Immunity"},{"key":"1588_CR12","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1038\/s41422-020-0277-x","volume":"30","author":"A Schnell","year":"2020","unstructured":"Schnell, A., Bod, L., Madi, A. & Kuchroo, V. K. The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity. Cell Res. 30, 285\u2013299 (2020).","journal-title":"Cell Res."},{"key":"1588_CR13","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/nri3862","volume":"15","author":"EJ Wherry","year":"2015","unstructured":"Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486\u2013499 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"1588_CR14","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1038\/s41590-018-0045-y","volume":"19","author":"EF McKinney","year":"2018","unstructured":"McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213\u2013221 (2018).","journal-title":"Nat. Immunol."},{"key":"1588_CR15","doi-asserted-by":"publisher","first-page":"101","DOI":"10.3109\/03009742.2013.823517","volume":"43","author":"SR Greisen","year":"2014","unstructured":"Greisen, S. R. et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand. J. Rheumatol. 43, 101\u2013108 (2014).","journal-title":"Scand. J. Rheumatol."},{"key":"1588_CR16","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s40425-018-0417-8","volume":"6","author":"KF Moseley","year":"2018","unstructured":"Moseley, K. F. et al. Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series. J. Immunother. Cancer 6, 104 (2018).","journal-title":"J. Immunother. Cancer"},{"key":"1588_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-02892-y","volume":"9","author":"F Mizoguchi","year":"2018","unstructured":"Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).","journal-title":"Nat. Commun."},{"key":"1588_CR18","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1038\/s41584-018-0112-7","volume":"14","author":"SG Dakin","year":"2018","unstructured":"Dakin, S. G. et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat. Rev. Rheumatol. 14, 714\u2013726 (2018).","journal-title":"Nat. Rev. Rheumatol."},{"key":"1588_CR19","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1111\/apm.12416","volume":"123","author":"SR Greisen","year":"2015","unstructured":"Greisen, S. R. et al. Spontaneous generation of functional osteoclasts from synovial fluid mononuclear cells as a model of inflammatory osteoclastogenesis. APMIS 123, 779\u2013786 (2015).","journal-title":"APMIS"},{"key":"1588_CR20","doi-asserted-by":"publisher","first-page":"2262","DOI":"10.1002\/art.38055","volume":"65","author":"EM Schmidt","year":"2013","unstructured":"Schmidt, E. M. et al. Selective blockade of tumor necrosis factor receptor I inhibits proinflammatory cytokine and chemokine production in human rheumatoid arthritis synovial membrane cell cultures. Arthritis Rheum. 65, 2262\u20132273 (2013).","journal-title":"Arthritis Rheum."},{"key":"1588_CR21","doi-asserted-by":"publisher","DOI":"10.1186\/2193-1801-2-263","volume":"2","author":"TW Kragstrup","year":"2013","unstructured":"Kragstrup, T. W., Vorup-Jensen, T., Deleuran, B. & Hvid, M. A simple set of validation steps identifies and removes false results in a sandwich enzyme-linked immunosorbent assay caused by anti-animal IgG antibodies in plasma from arthritis patients. SpringerPlus 2, 263 (2013).","journal-title":"SpringerPlus"},{"key":"1588_CR22","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1089\/dna.1995.14.741","volume":"14","author":"D Qu","year":"1995","unstructured":"Qu, D. & Green, M. Folding and assembly of a human MHC class II molecule in a cell-free system. DNA Cell Biol. 14, 741\u2013751 (1995).","journal-title":"DNA Cell Biol."},{"key":"1588_CR23","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1007\/BF00241263","volume":"39","author":"B Huard","year":"1994","unstructured":"Huard, B., Gaulard, P., Faure, F., Hercend, T. & Triebel, F. Cellular expression and tissue distribution of the human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics 39, 213\u2013217 (1994).","journal-title":"Immunogenetics"},{"key":"1588_CR24","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1002\/eji.200526090","volume":"35","author":"M Kisielow","year":"2005","unstructured":"Kisielow, M., Kisielow, J., Capoferri-Sollami, G. & Karjalainen, K. Expression of lymphocyte activation gene 3 (LAG-3) on B cells is induced by T cells. Eur. J. Immunol. 35, 2081\u20132088 (2005).","journal-title":"Eur. J. Immunol."},{"key":"1588_CR25","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.4049\/jimmunol.0800185","volume":"182","author":"CJ Workman","year":"2009","unstructured":"Workman, C. J. et al. LAG-3 regulates plasmacytoid dendritic cell homeostasis. J. Immunol. 182, 1885\u20131891 (2009).","journal-title":"J. Immunol."},{"key":"1588_CR26","doi-asserted-by":"crossref","unstructured":"Ellis, J. et al. Depletion of LAG-3(+) T cells translated to pharmacology and improvement in psoriasis disease activity: a Phase I Randomized Study of mAb GSK2831781. Clin. Pharmacol. Ther. 109, 1293\u20131303 (2021).","DOI":"10.1002\/cpt.2091"},{"key":"1588_CR27","doi-asserted-by":"publisher","first-page":"4669","DOI":"10.1172\/JCI96107","volume":"128","author":"A Petrelli","year":"2018","unstructured":"Petrelli, A. et al. PD-1+CD8+ T cells are clonally expanding effectors in human chronic inflammation. J. Clin. Invest. 128, 4669\u20134681 (2018).","journal-title":"J. Clin. Invest."},{"key":"1588_CR28","doi-asserted-by":"publisher","first-page":"2037","DOI":"10.1136\/ard.2010.145151","volume":"70","author":"A Ronaghy","year":"2011","unstructured":"Ronaghy, A. et al. Vaccination leads to an aberrant FOXP3 T-cell response in non-remitting juvenile idiopathic arthritis. Ann. Rheum. Dis. 70, 2037\u20132043 (2011).","journal-title":"Ann. Rheum. Dis."},{"key":"1588_CR29","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1016\/j.jaci.2016.04.013","volume":"138","author":"T Frenz","year":"2016","unstructured":"Frenz, T. et al. CD4(+) T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion. J. Allergy Clin. Immunol. 138, 586\u2013589 (2016).","journal-title":"J. Allergy Clin. Immunol."},{"key":"1588_CR30","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.immuni.2004.08.010","volume":"21","author":"CT Huang","year":"2004","unstructured":"Huang, C. T. et al. Role of LAG-3 in regulatory T cells. Immunity 21, 503\u2013513 (2004).","journal-title":"Immunity"},{"key":"1588_CR31","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1002\/art.39606","volume":"68","author":"LA Henderson","year":"2016","unstructured":"Henderson, L. A. et al. Next-generation sequencing reveals restriction and clonotypic expansion of Treg cells in juvenile idiopathic arthritis. Arthritis Rheumatol. 68, 1758\u20131768 (2016).","journal-title":"Arthritis Rheumatol."},{"key":"1588_CR32","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1136\/annrheumdis-2018-214229","volume":"78","author":"M Rosenzwajg","year":"2019","unstructured":"Rosenzwajg, M. et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann. Rheum. Dis. 78, 209\u2013217 (2019).","journal-title":"Ann. Rheum. Dis."},{"key":"1588_CR33","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1002\/art.27431","volume":"62","author":"N Ruperto","year":"2010","unstructured":"Ruperto, N. et al. Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis Rheumatol. 62, 1792\u20131802 (2010).","journal-title":"Arthritis Rheumatol."},{"key":"1588_CR34","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1002\/art.40466","volume":"70","author":"H Brunner","year":"2018","unstructured":"Brunner, H. et al. Subcutaneous abatacept in patients with polyarticular-course juvenile idiopathic arthritis: results from a Phase III Open-Label Study. Arthritis Rheumatol. 70, 144\u20131154 (2018).","journal-title":"Arthritis Rheumatol."},{"key":"1588_CR35","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1159\/000450948","volume":"171","author":"L Maggi","year":"2016","unstructured":"Maggi, L. et al. Immunosuppressive activity of abatacept on circulating T helper lymphocytes from juvenile idiopathic arthritis patients. Int. Arch. Allergy Immunol. 171, 45\u201353 (2016).","journal-title":"Int. Arch. Allergy Immunol."},{"key":"1588_CR36","doi-asserted-by":"publisher","first-page":"566","DOI":"10.1002\/art.40399","volume":"70","author":"M Fleury","year":"2018","unstructured":"Fleury, M. et al. Increased expression and modulated regulatory activity of coinhibitory receptors PD-1, TIGIT, and TIM-3 in lymphocytes from patients with systemic sclerosis. Arthritis Rheumatol. 70, 566\u2013577 (2018).","journal-title":"Arthritis Rheumatol."},{"key":"1588_CR37","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1056\/NEJMra1703481","volume":"378","author":"MA Postow","year":"2018","unstructured":"Postow, M. A., Sidlow, R. & Hellmann, M. D. Immune-related adverse events associated with immune checkpoint blockade. N. Engl. J. Med. 378, 158\u2013168 (2018).","journal-title":"N. Engl. J. Med."},{"key":"1588_CR38","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1038\/nrclinonc.2016.58","volume":"13","author":"C Boutros","year":"2016","unstructured":"Boutros, C. et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat. Rev. Clin. Oncol. 13, 473\u2013486 (2016).","journal-title":"Nat. Rev. Clin. Oncol."}],"container-title":["Pediatric Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01588-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01588-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01588-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T08:09:44Z","timestamp":1635926984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41390-021-01588-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,24]]},"references-count":38,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["1588"],"URL":"https:\/\/doi.org\/10.1038\/s41390-021-01588-2","relation":{},"ISSN":["0031-3998","1530-0447"],"issn-type":[{"value":"0031-3998","type":"print"},{"value":"1530-0447","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,24]]},"assertion":[{"value":"26 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 April 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"Written informed written consent for publication was obtained from the parents and patients.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"This study was approved by the Hacettepe University Ethics Committee for Non-Interventional Clinical Trials (GO 18\/277-35), and informed written consent to participate in the study was obtained from the parents and patients.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval and consent to participate"}}]}}